The present invention relates to novel crystalline forms of atorvastatin which is known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, as well as methods of using such compositions to treat subjects, including human subjects, suffering from hyperlipidemia, hypercholesterolemia, osteoporosis, and Alzheimer""s disease.
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitor(copyright) having the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate and the formula 
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent.
U.S. Pat. No. 4,681,893, which is incorporated herein by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (xc2x1)-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Pat. No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, ie, [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid which is atorvastatin.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,998,633; and 6,087,511, which are herein incorporated by reference, disclose various processes and key intermediates for preparing amorphous atorvastatin. Amorphous atorvastatin has unsuitable filtration and drying characteristics for large-scale production and must be protected from heat, light, oxygen, and moisture.
Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference.
International Published Patent Application Number WO 01/36384 allegedly discloses a polymorphic form of atorvastatin calcium.
Stable oral formulations of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,686,104 and 6,126,971.
Atorvastatin is prepared as its calcium salt, ie, [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2, xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). The calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration. Additionally, there is a need to produce atorvastatin in a pure and crystalline form to enable formulations to meet exacting pharmaceutical requirements and specifications.
Furthermore, the process by which atorvastatin is produced needs to be one which is amenable to large-scale production. Additionally, it is desirable that the product should be in a form that is readily filterable and easily dried. Finally, it is economically desirable that the product be stable for extended periods of time without the need for specialized storage conditions.
We have now surprisingly and unexpectedly found novel crystalline forms of atorvastatin. Thus, the present invention provides atorvastatin in new crystalline forms designated Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, and XIX. The new crystalline forms of atorvastatin are purer, more stable, or have advantageous manufacturing properties than the amorphous product.
Accordingly, the present invention is directed to crystalline Form V atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form V atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
Further, the present invention is directed to crystalline Form V atorvastatin and hydrates thereof characterized by the following solid-state 13C nuclear magnetic resonance (ssNMR) spectrum wherein chemical shift is expressed in parts per million:
Additionally, the present invention is directed to crystalline Form V atorvastatin and hydrates thereof characterized by the following Raman spectrum having peaks expressed in cm-xe2x88x921:
In a preferred embodiment of the first aspect of the invention, crystalline Form V atorvastatin is a trihydrate.
In a second aspect, the present invention is directed to crystalline Form VI atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form VI atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
Further, the present invention is directed to crystalline Form VI atorvastatin and hydrates thereof characterized by the following solid-state 13C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million:
In a third aspect, the present invention is directed to crystalline Form VII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form VII atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
Further, the present invention is directed to crystalline Form VII atorvastatin and hydrates thereof characterized by the following solid-state 13C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million:
Additionally, the present invention is directed to crystalline Form VII atorvastatin and hydrates thereof characterized by the following Raman spectrum having peaks expressed in cmxe2x88x921:
In a preferred embodiment of the third aspect of the invention, crystalline Form VII atorvastatin is a sesquihydrate.
In a fourth aspect, the present invention is directed to crystalline Form VIII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form VIII atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
Further, the present invention is directed to crystalline Form VIII atorvastatin and hydrates thereof characterized by the following solid-state 13C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million:
Additionally, the present invention is directed to crystalline Form VIII atorvastatin and hydrates thereof characterized by the following Raman spectrum having peaks expressed in cmxe2x88x921:
In a preferred embodiment of the fourth aspect of the invention, crystalline Form VIII atorvastatin is a dihydrate.
In a fifth aspect, the present invention is directed to crystalline Form IX atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form IX atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
In a sixth aspect, the present invention is directed to crystalline Form X atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form X atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
Further, the present invention is directed to crystalline Form X atorvastatin and hydrates thereof characterized by the following solid-state 13C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million:
Additionally, the present invention is directed crystalline Form X atorvastatin and hydrates thereof characterized by the following Raman spectrum having peaks expressed in cmxe2x88x921:
In a preferred embodiment of the sixth aspect of the invention, crystalline Form X atorvastatin is a trihydrate.
In a seventh aspect, the present invention is directed to crystalline Form XI atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
In an eighth aspect, the present invention is directed to crystalline Form XII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form XII atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
Additionally, the present invention is directed crystalline Form XII atorvastatin and hydrates thereof characterized by the following Raman spectrum having peaks expressed in cmxe2x88x921:
In a ninth aspect, the present invention is directed to crystalline Form XIII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Shimadzu diffractometer with CuKxcex1 radiation:
In a tenth aspect, the present invention is directed to crystalline Form XIV atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Bruker D5000 diffractometer with CuKxcex1 radiation:
In an eleventh aspect, the present invention is directed to crystalline Form XV atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Bruker D5000 diffractometer with CuKxcex1 radiation:
In a twelfth aspect, the present invention is directed to crystalline Form XVI atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Bruker D5000 diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form XVI atorvastatin expressed in terms of the 2xcex8 values was measured on a Shimadzu diffractometer with CuKxcex1 radiation:
In addition, the following X-ray powder diffraction pattern of crystalline Form XVI atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
In a thirteenth aspect, the present invention is directed to crystalline Form XVII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Bruker D5000 diffractometer with CuKxcex1 radiation:
In a fourteenth aspect, the present invention is directed to crystalline Form XVIII atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Bruker D5000 diffractometer with CuKxcex1 radiation:
Additionally, the following X-ray powder diffraction pattern of crystalline Form XVIII atorvastatin expressed in terms of the 2xcex8 values was measured on a Shimadzu diffractometer with CuKxcex1 radiation:
In addition, the following X-ray powder diffraction pattern of crystalline Form XVIII atorvastatin expressed in terms of the 2xcex8 values was measured on an Inel (capillary) diffractometer:
In a fifteenth aspect, the present invention is directed to crystalline Form XIX atorvastatin and hydrates thereof characterized by the following X-ray powder diffraction pattern expressed in terms of the 2xcex8 and relative intensities with a relative intensity of  greater than 10% measured on a Bruker D5000 diffractometer with CuKxcex1 radiation:
As inhibitors of HMG-CoA reductase, the novel crystalline forms of atorvastatin are useful hypolipidemic and hypocholesterolemic agents as well as agents in the treatment of osteoporosis and Alzheimer""s disease.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of crystalline Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX atorvastatin in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX atorvastatin.